EC50 - Wikipedia
Are they proportional? Is it possible for a drug to be potent yet have high Ki? Potency is related to the effective concentration (EC50). The EC50 .. What is the difference between IC50, Ki and Kd of a given inhibitor in an assay? Question. What is Pharmacodynamics Drug response curve EC50 Potency Efficacy Refrences; 4. Pharmacodynacmics describes the action. In the field of pharmacology, potency is a measure of drug activity expressed in terms of the Efficacy is the relationship between receptor occupancy and the ability to The concentration of A at which E is 50% of Emax is termed the half maximal effective concentration and is abbreviated [A]50, or more commonly EC
The concept but not the term "absolute IC50" is used to quantify drugs that slow cell growth.
The abbreviation GI50 is used for what we call here the absolute IC They don't use the terms relative and absolute. Incomplete dose-response curves Any attempt to determine an IC50 by fitting a curve to the data in the graph above will be useless.
A curve fitting program might, or might not, be able to fit a dose-response curve to the data. But if the curve fits, the value of the IC50 is likely to be meaningless and have a very wide confidence interval. The data simply don't form a top plateau which would define or a bottom plateau which would define 0.
If data haven't defined or 0, then 50 is undefined too, as is the IC If you also have control values that define and 0, then the curve can be easily fit. The curve below was created by fitting a dose response curve, but constraining the Top plateau to be a constant value equal to the mean of the Blanks values, and the Bottom plateau equal to the mean of the NS values.
The value of the IC50 fit this way only makes sense if you assume that higher concentrations of the inhibitor would eventually inhibit down to the NS values. That is an assumption that can't be tested with the data at hand.
The distinction between relative and absolute IC50 doesn't really apply to these data. Because the data don't define a bottom plateau, the IC50 must be defined relative to the NS control values. You can fit curves using data in their natural units. A common mistake is to assume that fitting dose-response curves requires that data first be normalized. There are three strategies you can use: From external controls Blank and NS in the figures above.
Since these values are so important, consider measuring these controls with more replicates than used for the rest of the experiment. From very low and very high concentrations of the test substance. Two fundamental properties of agonists are affinity and efficacy. Affinity can be defined as the tenacity with which a drug binds to its receptor. In statistical terms, it can be defined as the probability that a drug molecule will bind to an available receptor at any given instant in time.
Efficacy is an inherent property of an agonist that determines its ability to produce its biological effect. By definition, it is a property of the drug, not the receptor or tissue. Affinity gets the drug bound to the receptor, and efficacy determines what happens once the drug is bound. The term potency is used as a comparative term for distinguishing which agonist has a higher affinity for a given receptor Figure 2. Schematic illustration of the dose-response curves for a series of agonists A, B, C and D that have the same efficacy, but differ in terms of their potency.
Agonists can also differ in terms of their efficacy, or maximum response.
BASIC PRINCIPLES OF PHARMACOLOGY
Figure 4 shows a plot of four agonists that differ in terms of their relative efficacy. Drug A is the most efficacious, and Drug D the least. Drugs that bind to a receptor, but produce less than maximal activation e. Dose-response relationships for four agonists that vary in efficacy. Each drug has essentially the same EC50 value equi-potentbut differ in terms of the maximum response they can produce at high concentrations that saturate all available receptor sites.
Clinical Examples of Partial Agonists Clinically used examples of partial agonists include: Schizophrenia is a condition associated with both excess dopamine activity in one area of the brain resulting in hallucinations and delusionsas well as a co-existing reduced dopamine activity in another area causing cognitive impairment.
Aripiprazole is thought to produce beneficial effects in schizophrenia by exerting agonist effects in areas of dopamine deficit, while exerting sufficient antagonist effects in areas of dopamine hyperactivity. The presence of ISA results in a neutral effect on heart rate and cardiac output when the sympathetic nervous system is not activated e. They may be an appropriate choice for patients who require a beta blocker e. They are generally considered undesirable for use in patients who have previously had an myocardial infarction, since this may interfere with their otherwise anti-ischemic properties on the heart.
Signal Transduction Mechanisms for Agonists Once an agonist has bound to its receptor, its effects are transduced into a cellular response by one of several different mechanisms. A few of the most common mechanisms include: Examples of these mechanisms are shown below. Direct activation of an ion channel The drug receptor is structurally attached to an ion channel.
This results in a flow of channel permeant ions e.
50% of what? How exactly are IC50 and EC50 defined? - FAQ - GraphPad
Na and K for nicotinic receptors down their electrochemical gradient with a resultant change in membrane potential Figure 5. In skeletal muscle, this results in a depolarization of the membrane potential, the production of an action potential, and contraction the biological response.
G-protein activation of an ion channel The drug receptor stimulates an ion channel via activation of a G protein Figure 6. As an example, this is the mechanism by which acetylcholine acts to slow the heart rate. G-protein activated ion channel.
Binding of an agonist to the m2 receptor activates a G-protein Gi which in turn stimulates a K-selective channel to open. The increase in K permeability will hyperpolarize the membrane potential.
G-protein activation of a second messenger cascade There are two well characterized second messenger cascade mechanisms. One involves the G-protein Gs mediated activation of adenylyl cyclase, with subsequent formation of camp and activation of protein kinase A PK-A Figure 7. DAG acts as a second messenger to stimulate protein kinase C, and IP3 stimulates the release of Ca ions from intracellular stores.
DAG acts as a second messenger to activate protein kinase C PK-Cwhich phosphorylates a variety of intracellular proteins. IP3 stimulates the release of Ca from intracellular stores. These mechanisms are believed to mediate the vasoconstrictive effects of Ang II on vascular smooth muscle. Receptors linked to Cytoplasmic Enzymes e. These receptors contain an extracellular domain that binds to a specific ligand, and a cytoplasmic domain that typically contains a protein tyrosine kinase Figure 9.
However, other enzymes such as serine kinases, or a guanylyl cyclase may also be coupled to a receptor and work by the same mechanism. EGF, Insulin, various growth factors Figure 9.
The binding of a ligand to receptors produces a change in receptor conformation that allows receptors to interact. The auto-phosphorylation typically results in a prolonged response to the agonist e. Noncompetitive Antagonists Antagonists are drugs that bind to receptors have affinitybut do not produce a substantial degree of receptor stimulation they have very low efficacy.
Antagonists are typically classified as competitive or noncompetitive. Competitive antagonists bind reversibly to the same receptor site as the agonist. This effect produces a rightward parallel shift of the dose-response for the agonist towards higher concentrations.
In the presence of a competitive antagonist, agonists can still produce the same e. The vast majority of clinically used drugs that act as receptor antagonists are competitive antagonists. Noncompetitive antagonists either bind irreversibly e.
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Unsourced or poorly sourced material may be challenged and removed. March Learn how and when to remove this template message In the field of pharmacologypotency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. The potency depends on both the affinity and efficacy. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.
In other words, efficacy refers to how well an action is took after the drug is bound to a receptor. In pharmacology, a high efficacy usually means that a drug has worked since the drug caused the receptor to metabolize a certain compound extremely well.